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YAP forms autocrine loops with the ERBB pathway to regulate ovarian cancer initiation and progression

Oncogene volume 34, pages 6040–6054 (2015)Cite this article

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Abstract

Mechanisms underlying ovarian cancer initiation and progression are unclear. Herein, we report that the Yes-associated protein (YAP), a major effector of the Hippo tumor suppressor pathway, interacts with ERBB signaling pathways to regulate the initiation and progression of ovarian cancer. Immunohistochemistry studies indicate that YAP expression is associated with poor clinical outcomes in patients. Overexpression or constitutive activation of YAP leads to transformation and tumorigenesis in human ovarian surface epithelial cells, and promotes growth of cancer cells in vivo and in vitro. YAP induces the expression of epidermal growth factor (EGF) receptors (EGFR, ERBB3) and production of EGF-like ligands (HBEGF, NRG1 and NRG2). HBEGF or NRG1, in turn, activates YAP and stimulates cancer cell growth. Knockdown of ERBB3 or HBEGF eliminates YAP effects on cell growth and transformation, whereas knockdown of YAP abrogates NRG1- and HBEGF-stimulated cell proliferation. Collectively, our study demonstrates the existence of HBEGF & NRGs/ERBBs/YAP/HBEGF & NRGs autocrine loop that controls ovarian cell tumorigenesis and cancer progression.

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Acknowledgements

This work was supported by the Eunice Kennedy Shriver National Institute of Child Health and Human Development (5R00HD059985, 5P01AG029531); The Olson Center for Women’s Health (no number); The Fred & Pamela Buffett Cancer Center (LB595); the Omaha Veterans Administration Medical Center (5I01BX000512) and The National Institute of Food and Agriculture (2011-67015-20076). We wish to thank for Melody A. Montgomery at the University of Nebraska Medical Center Research Editorial Office for her professional assistance in editing this manuscript.

Author Contributions

CH contributed to the design, performance, data analysis and manuscript preparation. XL packaged the retrovirus and performed in vivo experiments. GH conducted IHC analysis. JD constructed the retroviral vectors. SL and SR evaluated and analyzed patient samples. JSD contributed to the experimental design, results, discussion and manuscript preparation. CW supervised these studies and contributed to the experimental design, data analysis and manuscript preparation.

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Authors and Affiliations

  1. Department of Obstetrics and Gynecology, Olson Center for Women’s Health, University of Nebraska Medical Center, Omaha, NE, USA

    C He, X Lv, G Hua, S Remmenga, J S Davis & C Wang

  2. College of Animal Sciences and Technology, Huazhong Agricultural University, Wuhan, Hubei province, P.R. China

    C He & G Hua

  3. Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, NE, USA

    S M Lele

  4. Fred & Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, NE, USA

    S Remmenga, J Dong, J S Davis & C Wang

  5. Omaha Veterans Affairs Medical Center, Omaha, NE, USA

    J S Davis

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Correspondence to C Wang.

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He, C., Lv, X., Hua, G. et al. YAP forms autocrine loops with the ERBB pathway to regulate ovarian cancer initiation and progression. Oncogene 34, 6040–6054 (2015). https://doi.org/10.1038/onc.2015.52

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